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Every year, 16,000 cases of lupus are reported in the United States — 9 out of 10 of them in women. Scientists have long believed sex differences help explain women’s predisposition for the autoimmune disease. But researchers said last week that they may now have one explanation for why exactly the presence of two X chromosomes increases the chances that a person will develop lupus.

Dozens of genes have been associated with lupus, but in a new study, researchers focused on the overexpression of the gene Tlr7, which sits on the X chromosome.


In women’s cells, genes on one of the X chromosomes become inactivated as a way of controlling gene expression. In the study, published Friday in the journal Science Immunology, a team of French scientists found that Tlr7 can evade attempts to limit its expression.

“This was a hypothesis that you found in many reviews, but it had never been demonstrated,” said Jean-Charles Guéry, a study author and scientist at Inserm, France’s equivalent of the National Institutes of Health.

Patients with lupus suffer from pain, fever, and rashes in different parts of their bodies, with the symptoms coming and going as the disease flares. There is no cure, but it is managed with medications that target inflammation and tamp down immune system activity.


For their study, researchers studied the immune cells of healthy women, measuring the expression of Tlr7. They found that in some cells, both copies of the gene were making the protein TLR7. They found the same pattern of dual expression when studying cells of men who have an extra X chromosome, what is called Klinefelter syndrome. (Men with Klinefelter syndrome develop lupus at much higher rates than other men.)

That indicated that Tlr7 was able to avoid X chromosome inactivation.

The researchers also discovered that the overexpression of Tlr7 — what is called biallelism, because both alleles are being expressed — led to changes in the cells and the proteins they produce that could induce autoimmune issues. The protein TLR7 normally plays a role in helping the immune system identify viral infections, but in past animal studies, researchers have found that when immune cells produce excess TLR7, the animals can develop their version of lupus.

Dr. Hal Scofield, an autoimmune disease expert at the Oklahoma Medical Research Foundation who was not involved in the new study, said it bolstered the belief that having more TLR7 increases the chances of developing lupus. But he noted that there are dozens of genes associated with lupus, and that even people genetically predisposed to the disease might not develop it.

Still, Scofield said, the study pointed to the importance of X chromosome inactivation, which has often been underestimated. He said that if both copies of Tlr7 are expressed, then maybe other, related genes also associated with lupus get overexpressed.

“Given all the genes that escape X inactivation, there might be others,” he said. “You might find others that interact with TLR7. You might find a whole cascade.”

Guéry said he and his team next plan to compare TLR7 levels in healthy women with those in lupus patients. He wondered, for example, if higher levels of the protein might be correlated to the severity of the disease or the onset of flares of symptoms.

Guéry said his research did not show how or why exactly Tlr7 avoids X chromosome inactivation, but that it suggested limiting TLR7 levels might offer a new therapeutic avenue to treating lupus — a step that would be easier than trying to inactivate the second copy of the Tlr7 gene.

“It’s true that if we can reestablish inactivation of the X chromosome, that might be good for patients,” he said. “But what might be better is to target TLR7 directly.”

  • I think you should at least correctly describe what lupus is. You add to the confusion by handing out a few symptoms and ignoring the need to educate many on this little known, horrendous, debilitating disease.

    Lupus is a disease of hyperactivity of the immune system such that your own immune system attacks your body’s own tissues at the cellular level; mainly at joints but possible anywhere, including in smooth muscle tissues.

    Lupus comes in varying degrees from nuisance level, to functional arthritic-level, to bed confinement and debilitation level. The condition tends to wax and wane, often with the level of rest that the patient gets. Those who over-exert themselves or lack adequate sleep suffer flare ups where they temporarily become debilitated, even though they are normally functional. Lupus patients take the same medicines that those who suffer from arthritis take, and arthritis doctors are the doctors who treat this disease.

    It is not uncommon to hear that a woman has been basically home-bound for a period of years on account of this disease; unable to work, unable to find relief, and forced into a life of sudden disability.

    A key marker in the blood of these patients is ANA level, which loosely corresponds with severity of the disease. The presence of ANA means that your immune system contains a protein that adversely reacts with parts of your own body’s cells.

    Patients who suffer from lupus not only have predictable symptoms, but also wildly varying symptoms. One unpredictable symptom is smooth muscle spasms, even inside blood vessels, the intestine and esophagus. Out of nowhere, a lupus patient can feel intense pain from such a smooth muscle attack. These instances are treated with anti-spasmodic drugs and with certain medications that have the “off-label” effect of relaxing smooth muscle.

    Finally, lupus can attack the nerve tissues as well. Many lupus patients report suffering from the same tingling and stinging pains in their lower extremities that diabetics report when suffering neuropathy.

    • I know this story/comment is a year old, but I want to thank you, Steven Gottlieb, for such an accurate description of this disease. I suffer from each of the symptoms listed, have been disabled, mostly home bound and often bed bound for six years due to a combination of lupus and PsA. Your comment is the best description to date I’ve read of what my disease experience is like. Thank you for giving me, and others like myself, a voice.

    • Amy, I am heartbroken to hear of your suffering. I have had several women in my life suffer from this disease. My wife has a mild form. A female former co-worker has a near-debilitating case. A former client had a case where she was debilitated for a solid 5-year period. The disease is insidious and we must do more to isolate the cause, as well as develop a cure. I hope your case remits and you are able to live a more normal and more enjoyable life. I will pray that it shall be so. Best of luck to you and thank you for your kind remarks.

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